What Are Calcium Channel Blockers?

Calcium channel blockers, also known as calcium antagonists, are a class of drugs that can selectively block the flow of Ca2 + into cells through voltage-dependent calcium channels and reduce the concentration of Ca2 + in cells. Calcium channel blockers commonly used in clinical practice mainly include benzidines (such as verapamil, etc.), dihydropyridines (such as nifedipine, nifedipine, etc.), and diltiazem (such as diltiazem, diltiazem, etc.). Verapamil was the first calcium channel blocker to be discovered. In 1967, German Fleckenstein and others found that verapamil had a similar effect on the heart as Ca2 + was removed from the solution, and could reduce the contractility of the heart without affecting the change and amplitude of membrane potential, so it was called a calcium antagonist. Since then, a large number of calcium channel blockers have been used clinically.

Calcium channel blockers, also known as calcium antagonists, are a class of drugs that can selectively block the flow of Ca2 + into cells through voltage-dependent calcium channels and reduce the concentration of Ca2 + in cells. Calcium channel blockers commonly used in clinical practice mainly include benzidines (such as verapamil, etc.), dihydropyridines (such as nifedipine, nifedipine, etc.), and diltiazem (such as diltiazem, diltiazem, etc.). Verapamil was the first calcium channel blocker to be discovered. In 1967, German Fleckenstein and others found that verapamil had a similar effect on the heart as Ca2 + was removed from the solution, and could reduce the contractility of the heart without affecting the change and amplitude of membrane potential, so it was called a calcium antagonist. Since then, a large number of calcium channel blockers have been used clinically.

Drug Name

Calcium antagonist

Alias

Calcium channel blocker

Foreign name

Calcium Antagonists

Main indications

For hypertension, coronary heart disease and arrhythmias

Adverse reactions

8 items

Ca2+ Calcium channel blockers I. The role and source of intracellular Ca2 +

In the body, Ca2 + is widely involved in the biological response of tissue cells. To summarize, there are the following aspects:

Contraction of muscles (including skeletal muscle, cardiac muscle, and various smooth muscles).

Formation of autonomic action potentials of autonomic cells.

secretion of various glands.

platelet aggregation, release, contraction, cell row.

Mast cell release response (degranulation); movement of polymorphonuclear leukocytes, release of lysosomal enzymes.

Release of neurotransmitters.

When most tissues are damaged, intracellular Ca2 + increases. This state is called Ca2 + overload or Ca2 + overload. Ca2 + overload further aggravates cell damage.

Many tissue cells need to increase the free Ca2 + concentration in the cytoplasm to a certain level in order to produce a biological response. Because these calcium ions can stimulate cells, it is also called activator calcium. When the cells were at rest, the concentration of free Ca2 + in the cytoplasm was less than 1 mol / L, and the extracellular fluid was about 1.5 mmol / L. There are three main sources of stimulating calcium: transmembrane influx via potential dependent calcium channel (PDC); influx via receptor-operated calcium channel (ROC); from cells Released from internal storage or binding sites. These three sources often affect each other. Extracellular high potassium depolarizes the cell membrane, mainly by turning on the PDC to cause extracellular calcium ions to flow through the membrane through the PDC and cause biological effects. Bioactive substances, such as norepinephrine, histamine, serotonin, etc., can open the ROC, and at the same time, it can also open the PDC by changing the cell membrane potential. The calcium ions entering the cell via PDC and ROC can promote the release of intracellular calcium through the calcium-induced calcium release mechanism (CICR).

Activating calcium must be combined with "calcin-binding protein", and then through a series of processes, the cells will eventually produce biological effects. Therefore, any drug that can prevent the increase of intracellular calcium or block the binding of intracellular calcium to "calcin-binding protein" can be considered to have a calcium antagonistic effect. Classical calcium antagonists in the narrow sense refer to drugs that can selectively block calcium influx through potential-dependent channels across the membrane. Representative drugs include nifedipine, verapamil and diltiazem.

Calcium channel blockers 2. Types and structures of calcium channels

Receptor-regulated calcium channel (ROC, RECEPTOR OPERATED CALCIUM CHANNEL)

Voltage-dependent calcium channels (VDC, voltage-dependent calcium channels) are further divided into L-, N-, T-, P-, Q-, and R-types according to their different conductance values and dynamic characteristics. The cardiovascular system is mainly L-, T-type. Calcium antagonists act primarily on the L-type.

The L-type calcium channel consists of five subunits: 1, 2, , , and . Among them, 1 is a functional subunit, which has four repeating domains, each of which contains 6 transmembrane fragments, which are S1-S6. S4 is a small hole formed between the voltage-sensitive regions S5-S6 of the calcium channel for Ca2 + permeation.

Calcium Channel Blockers III. Basic Concepts and Mechanisms of Calcium Antagonists

Calcium antagonists (calcium antagonists) is a new class of drugs with important theoretical significance and practical value developed in the 1960s. At first, calcium antagonists narrowly referred to those drugs that selectively block the influx of Ca2 + via potential-dependent slow channels across cell membranes. Representative drugs include verapamil, nifedipine, and diltiazem. Although their chemical structures are different, they can block extracellular calcium ions from entering the cell through the slow channel on the cell membrane (because most of the ions that enter the cell through this channel are calcium ions, so called calcium channels). With the deepening of research, the concept of calcium antagonists has gradually expanded, and people like to fashionablely name the drugs that can inhibit the influx of Ca2 + across the membrane under the name of calcium antagonists. Calcium antagonists generally refer to drugs that have no obvious inhibitory effect on the biological effects caused by intracellular Ca2 + and do not significantly affect the release of intracellular calcium ions. Instead, they selectively block the calcium channels of the cell membrane and inhibit the extracellular Ca2 + influx. Decreasing the use of Ca2 + in cells to play a role, is an antagonist of calcium utilization. Therefore, this class of drugs is also called calcium channel blockers, calcium entry blockers, and calcium entry inhibitors.

Classification of calcium channel blockers IV. Calcium antagonists

Calcium antagonists have very different chemical structures and different pharmacological effects. With the deepening of research, more and more drugs are called calcium antagonists. In order to rationally use the drugs, the World Health Organization classifies calcium antagonists into two categories, selective and non-selective calcium antagonists; according to their chemical structure and Pharmacological effects are different, calcium antagonists are further divided into six categories.

1. Selective calcium channel blockers

Class I phenylalkylamines (PAAs): verapamil, gallopamil, tiapamil, etc.

Type II dihydropyridines (DHPs): nifedipine, nicardipine, nitrendipine, amlodipine, nimodipine, nisoldipine (nisoldipine) and so on.

Class III benzothiazepines (BTZs): diltiazem, clentiazem, diclofurine, and the like.

2. Non-selective calcium channel blockers

Class IV Flunarizine: Flunarizine, Cinnarizine, Lidoflazine, and the like.

Type V Punilamin: Prenylamine and so on.

Class VI others: perhexiline and the like.

Calcium channel blockers can also be divided into three generations according to the drug development trajectory and action characteristics:

The first generation of representative medicines are verapamil, nifedipine, diltiazem. It has stable efficacy and few adverse reactions, and is widely used in anti-arrhythmia, anti-hypertension, and prevention and treatment of angina pectoris.

The second generation of representative medicines are felodipine, nicardipine, nitrendipine, nimodipine and so on. Developed on the basis of the structure of dihydropyridine, this class of drugs has high selectivity, stable properties and precise curative effect.

The third generation of representative drugs are pranidipine, amlodipine, bepridil and so on. In addition to having a high degree of vascular selectivity, these drugs have the characteristics of long t1 / 2 and long-lasting effects.